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Novel mutations within the POU1F1 gene associated with variable Combined Pituitary Hormone Deficiency (CPHD) (2005)

Turton,
J.P.,
Reynaud,
R.,
Mehta,
A.,
Torpiano,
J.,
Saveanu,
A.,
Woods,
K.S.,
Tiulpakov,
A.,
Zdravkovic,
V.,
Hamilton,
J.,
Attard-Montalto,
S.,
Parascandalo,
R.,
Vella,
C.,
Clayton,
P.E.,
Shalet,
S.,
Barton,
J.,
Brue,
T.,
Dattani,
M.T.

Abstract

CONTEXT: Mutations within the gene encoding the pituitary-specific transcription factor POU1F1 are associated with combined pituitary hormone deficiency (CPHD). Most of the affected individuals manifest GH, prolactin and TSH deficiency. OBJECTIVE: We have now screened 129 individuals with CPHD and isolated growth hormone deficiency (IGHD) for mutations within POU1F1. RESULTS: Causative mutations were identified in 10/129 individuals (7.8%). Of these, 5 patients harbored the dominant negative R271W mutation, which is a well-recognized mutational "hot-spot". We have also identified a second frequently occurring mutation, E230K, which appears to be common in Maltese patients. Additionally, we describe two novel mutations within POU1F1, an insertion of a single bp (ins778A) and a missense mutation (R172Q). Functional studies have revealed that POU1F1 (E230K) is associated with a reduction in transactivation, although DNA-binding affinity is similar to the wild-type protein. On the other hand, POU1F1 (R172Q) is associated with a reduction in DNA-binding and transactivation, whereas POU1F1 (ins778A) is associated with loss of DNA-binding and a reduction in transactivation. CONCLUSIONS: Our data suggest that the phenotype associated with POU1F1 mutations may be more variable, with the occasional preservation of TSH secretion. Additionally, our data revealed POU1F1 mutations in 3 patients who were diagnosed as having ACTH deficiency, but who, on further evaluation, were found to have normal cortisol secretion. Hence, elucidation of the genotype led to further evaluation of the phenotype, with the cessation of cortisol replacement which had been commenced unnecessarily. These data reflect the importance of mutational analysis in patients with CPHD

Publication details

Repository	UCL Research Publications Index (MyOPIA) (United Kingdom)
Keywords	3, 5, A, Analysis, AND, ARTICLE, Canada, CHILD, child health, CHILDREN, CORTISOL, DEFICIENCY, DOMINANT, Endocrinology, Evaluation, FOR, France, GENE, Genotype, GROWTH, GROWTH HORMONE, GROWTH HORMONE DEFICIENCY, HAD, Hand, HEALTH, HORMONE, INDIVIDUALS, IS, Isolated Growth Hormone Deficiency, JOURNAL, LA, LONDON, METABOLISM, MISSENSE MUTATION, MUTATION, MUTATIONAL ANALYSIS, MUTATIONS, novel mutations, OF, Other, paediatric, PAEDIATRICS, PATIENT, patients, Phenotype, PITUITARY, PRESERVATION, Prolactin, PROTEIN, REPLACEMENT, Research, Result, RP, Russian, SECRETION, SINGLE, TB, THE, TRANSCRIPTION, Transcription Factor, UK, unit
Type	JOUR